Xu Xiaohan, Ren Jing, Li Jianchao
Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China.
Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou, China.
J Biol Chem. 2025 Jun 6;301(7):110346. doi: 10.1016/j.jbc.2025.110346.
BAR (Bin/Amphiphysin/Rvs) domain proteins drive membrane remodeling critical for cellular processes like ciliogenesis and organelle morphology. FAM92A (family with sequence similarity 92A), a classical BAR protein, regulates ciliary assembly, mitochondrial ultrastructure, and neuronal membrane dynamics, yet its molecular mechanisms remain elusive. Here, we determined the 2.2 Å crystal structure of the mouse FAM92A BAR domain, revealing an antiparallel, crescent-shaped homodimer. Structure-guided mutagenesis revealed that positively charged clusters on the concave surface are critical for lipid binding and identified residues essential for dimerization. We further demonstrated that FAM92A BAR directly binds the N-terminal region of Chibby1 (CBY1), a ciliary protein, with their respective dimerizations synergistically enhancing affinity. These findings elucidate the structural basis of FAM92A's membrane remodeling and CBY1 interaction, providing a molecular framework for its function in ciliogenesis and suggesting broader implications for FAM92 family proteins.
BAR（Bin/Amphiphysin/Rvs）结构域蛋白驱动膜重塑，这对纤毛发生和细胞器形态等细胞过程至关重要。FAM92A（序列相似性家族92A）是一种经典的BAR蛋白，可调节纤毛组装、线粒体超微结构和神经元膜动力学，但其分子机制仍不清楚。在这里，我们确定了小鼠FAM92A BAR结构域的2.2埃晶体结构，揭示了一个反平行的新月形同源二聚体。结构导向诱变表明，凹面上的带正电簇对脂质结合至关重要，并确定了二聚化所必需的残基。我们进一步证明，FAM92A BAR直接与纤毛蛋白Chibby1（CBY1）的N端区域结合，它们各自的二聚化协同增强亲和力。这些发现阐明了FAM92A膜重塑和与CBY1相互作用的结构基础，为其在纤毛发生中的功能提供了分子框架，并暗示了FAM92家族蛋白更广泛的意义。
